The present invention relates to a series of new .alpha.,.omega.-diarylalkane derivatives which are serotonin-2 receptor antagonists and which, therefore, are useful for the treatment and prevention of circulatory (cardiovascular) diseases and psychosis. The invention also provides methods and compositions using these novel compounds, as well as processes for their preparation.
Classically, serotonin has been grouped with the autacoids. A known neurotransmitter, serotonin exhibits many physiological actions in vivo which are mediated through diverse receptors. It is known that there are many subtypes of serotonin receptors. In the circulatory system, receptors classified as serotonin-2 receptors are distributed in the blood vessel endothelial cells and platelets, and these receptors are strongly implicated in vasoconstriction and platelet agglutination [e.g. S. J. Peroutka et al., Fed. Proc., 42, 213 (1983)]. Antagonists to these receptors are useful in preventing vasoconstriction and blocking platelet agglutination.
Recent reports have suggested the use of MCI-9042, which is a {2-[.omega.-aminoalkoxy)phenyl]ethyl}benzene, to block platelet agglutination based on its serotonin-2 receptor antagonist action [e.g. J. Med. Chem., 35, 189 (1992)].
Although these compounds do not exhibit any antagonistic effect on adrenaline-.alpha..sub.1, their antagonistic effect on serotonin-2 receptors and/or their platelet agglutination blocking effect is also insufficiently strong. Therefore, in order to achieve results at the clinical level, the development of a drug which had both a potent and selective antagonistic effect on serotonin-2 receptors was needed.
A number of compounds having generally a .alpha.,.omega.-diarylalkane structure has been proposed for the treatment of circulatory diseases, based on their platelet agglutination effects. Examples of such compounds are disclosed in European Patent Publications No. 1 759, 72 942 and 398 326, as well as in J. Med. Chem., 33, 1818 (1990) and the aforesaid J. Med. Chem., 35, 189 (1992).
We have surprisingly found that certain compounds of this type, as well as having unexpectedly improved serotonin-2 receptor antagonist activity leading to their use in the treatment and prophylaxis of circulatory diseases, also has unexpected dopamine-2 receptor antagonist activity, leading to their use in the treatment and prophylaxis of psychiatric conditions, notably psychosis.